The nature of the defect in cobalamin G mutation.

Cobalamin G mutation (cblG) typically presents as a severe megaloblastic anemia during the first few weeks of life. The anemia responds completely to treatment with high doses of Cbl but the neurologic manifestations respond more slowly and not always completely. Cultured fibroblasts from two affected infants and virus-transformed lymphoblasts from one of the infants expressed the following: poor growth in the absence of methionine, the ability to take up and internalize Cbl bound to transcobalamin II, impaired synthesis of methionine from homocysteine, the ability to bind incoming Cbl to the respective coenzymes, but an inability to synthesize methylcobalamin in spite of a normal capacity to synthesize adenosylcobalamin. The in vitro activity of the methyltransferase dependent on methylcobalamin of cell extracts varied from low to high depending on the conditions of culture and assay. The cblG cells were unusually sensitive to the concentration of adenosylmethionine in the assay. More adenosylmethionine was required by cblG cells to achieve the same level of enzyme activity as control cells and high concentrations of adenosylmethionine did not suppress activity as in control cells. It was postulated that the defect in cblG is in the metabolism of adenosylmethionine, an essential substance for the synthesis of methionine from homocysteine.